4-oxybenzopyran derivative

ABSTRACT

This invention relates to a 4-oxybenzopyran derivative of formula (I) wherein, R 1  and R 2  represent each independently a hydrogen atom, a C 1-6  alkyl group or a phenyl group; R 3  represents a hydroxyl group or a C 1-6  alkylcarbonyloxy group; R 4  represents a hydrogen atom, a C 3-6  cycloalkyl group, a C 1-6  alkyl group, a C 1-6  alkylcarbonyl group, a C 1-6  alkylaminocarbonyl group, a di-C 1-6  alkylaminocarbonyl group, an aryl group or a heteroaryl group; n represents an integer of 0-4; X represents —C(═O)NR 7 —, —NR 8 —, —NHC(═O)NH— or —S(O) 2 NH—; R5 represents a hydrogen atom or (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), or (l); R 6  represents a hydrogen atom, a halogen atom, a nitro group or a cyano group; or a pharmaceutically acceptable salt thereof. And this invention also relates to an antiarrhythmic agent having the prolongation effect of the functional refractory period comprising said compound or a pharmaceutically acceptable salt thereof as an active ingredient.

DESCRIPTION

1. Technical Field

The present invention relates to 4-oxybenzopyran derivatives having aprolongation effect on the functional refractory period, which are usedfor treatments of arrhythmia in mammal including human beings.

2. Background Art

As benzopyran derivatives, there have been known 4-acylaminobenzopyranderivatives exemplified by Cromakalim (Japanese Patent ApplicationLaid-Open No. Sho 58-67683). These 4-acylaminobenzopyran derivativesexemplified by Cromakalim are known to open an ATP sensitive K⁺channeland to be effective for the treatment of hypertension or asthma, butthere has not been any mention as to the treatment for arrhythmia basedon the prolongation effect on the functional refractory period.

Now, conventional antiarrhythmic agents having the prolongation effecton the functional refractory period as a main function (such as Class Idrugs of antiarrhythmic agent classification according to VaughanWilliams, or d-sotalol belonging to Class III) having highly dangerousarrhythmic inducing actions that can result in sudden death such astorsades de pointes based on extension of ventricular muscle actionpotential relating to the prolongation effect on the functionalrefractory period, which become the therapeutic problems. Thus, agentshaving less side effects are desired.

The inventors of the present invention have made an intensive study ofcompounds having the prolongation effect on the functional refractoryperiod more selective for atrium muscle than for ventricular muscle, andfound that the compound of the general formula (I) has a prolongationeffect on the functional refractory period selective for atrium musclewithout any influence on the refractory period of ventricular muscle andaction potential parameters.

DISCLOSURE OF INVENTION

The inventors of the present invention have studied eagerly4-oxybenzopyran derivatives, and found that the compound of the formula(I) has the strong prolongation effect on the functional refractoryperiod, and it is useful as an antiarrhythmic agent. The presentinvention has been made based on this finding.

The present invention relates to a 4-oxybenzopyran derivative of theformula (I)

wherein, R¹ and R² represent each independently a hydrogen atom; a C₁₋₆alkyl group in which said alkyl group may be optionally substituted witha halogen atom, a C₁₋₆ alkoxy group or a hydroxyl group; or a phenylgroup in which said phenyl group may be optionally substituted with ahalogen atom, a hydroxyl group, a nitro group, a cyano group, a C₁₋₆alkyl group or a C₁₋₆ alkoxy group;

R³ represents a hydroxyl group or a C₁₋₆ alkylcarbonyloxy group;

R⁴ represents a hydrogen atom, a C₃₋₆ cycloalkyl group, a C₁₋₆ alkylgroup, a C₁₋₆ alkylcarbonyl group, a C₁₋₆ alkylaminocarbonyl group or adi-C₁₋₆ alkylaminocarbonyl group in which said C₁₋₆ alkyl group, saidC₁₋₆ alkylcarbonyl groups, said C₁₋₆ alkylaminocarbonyl group and saiddi-C₁₋₆ alkylaminocarbonyl group may be each optionally substituted witha halogen atom, a C₁₋₆ alkoxy group, a C₁₋₆ alkoxy group substituted bya halogen atom; a carboxyl group, a C₁₋₆ alkoxycarbonyl group, ahydroxyl group, or an aryl group or a heteroaryl group; in which saidaryl group and said heteroaryl group may be optionally substituted with(R⁹)₄, in which R⁹ represents a halogen atom, a hydroxyl group, a C₁₋₆alkyl group, a C₁₋₆ alkyl group substituted by a halogen atom or a C₁₋₆alkoxy group; a C₁₋₆ alkoxy group, A C₁₋₆ alkoxy group substituted by ahalogen atom; or R⁹ represents a nitro group, a cyano group, a formylgroup, a formamide group, an amino group, a C₁₋₆ alkylamino group, adi-C₁₋₆ alkylamino group, a C₁₋₆ alkylcarbonylamino group, a C₁₋₆alkylsulfonylamino group, an aminocarbonyl group, a C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group, a C₁₋₆alkylcarbonyl group, a C₁₋₆ alkoxycarbonyl group, an aminosulfonylgroup, a C₁₋₆ alkylsulfonyl group, a carboxyl group or an arylcarbonylgroup if r represents 2 r 3; or R⁴ represents an aryl group or aheteroaryl group in which said aryl group and said heteroaryl group maybe optionally substituted with (R¹⁰)_(q) in which R¹⁰ has the samemeaning as R⁹, q represents an integer of 1-3, and each R¹⁰ may be sameor different if q represents 2 or 3;

n represents an integer of 0-4;

X represents —C(═O)NR⁷—, —NR⁸—, —NHC(═O)NH— or —S(O)₂NH— (in which R⁷and R⁸ represent each independently a hydrogen atom or a C₁₋₆ alkylgroup);

R⁵ represents a hydrogen atom; or a group of the formula:

in which R¹² represents a hydrogen atom; a halogen atom; a C₁₋₆ alkylgroup in which the alkyl group may be optionally substituted with ahalogen atom or a C₁₋₆ alkoxy group; a C₁₋₆ alkoxy group in which saidalkoxy group may be optionally substituted with a halogen atom; a phenylgroup in which said phenyl group may be optionally substituted with ahalogen atom, a hydroxyl group, a C₁₋₆ alkyl group or a C₁₋₆ alkoxygroup; or R¹² represents a hydroxyl group, a nitro group, a cyano group,a formyl group, a formamide group, an amino group, a C₁₋₆ alkylaminogroup, a di-C₁₋₆ alkylamino group, a C₁₋₆ alkylcarbonylamino group, aC₁₋₆ alkylsulfonylamino group, an aminocarbonyl group, a C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group, a C₁₋₆alkylcarbonyl group, a C₁₋₆ alkoxycarbonyl group, an aminosulfonylgroup, a C₁₋₆ alkylsulfonyl group, a carboxyl group or an arylcarbonylgroup, m represents an integer of 1-3, and each R¹² may be same ordifferent if m represents 2 or 3, and R¹³ represents a hydrogen atom ora C₁₋₆ alkyl group; and

R⁶ represents a hydrogen atom, a halogen atom, a nitro group or a cyanogroup;

or a pharmaceutically acceptable salt thereof.

The compound according to the present invention has the strongprolongation effect on the functional refractory period and it can beused as a drug for treating arrhythmia.

Respective substituents for the compound (I) according to the presentinvention are illustrated specifically as follows.

Herein, “n” means normal, “i” means iso, “s” means secondary, “t” meanstertiary, “c” means cyclo, “o” means ortho, “m” means meta, and “p”means para.

As C₁₋₆ alkyl groups, there may be mentioned methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 1-pentyl, 2-pentyl,3-pentyl, i-pentyl, neopentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl,3-hexyl, 1-methyl-n-pentyl, 1,1,2-trimethyl-n-propyl,1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl, trifluoromethyl,trifluoroethyl, pentafluoroethyl, cyanomethyl and hydroxymethyl, etc.

Preferably, there may be mentioned methyl, ethyl, n-propyl, i-propyl andn-butyl.

As halogen atoms, there may be mentioned a fluorine atom, a chlorineatom, a bromine atom and an iodine atom. Preferably, there may bementioned a fluorine atom, a chlorine atom and a bromine atom.

As C₁₋₆ alkoxy groups, there may be mentioned methoxy, trifluoromethoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy,1-pentyloxy, 2-pentyloxy, 3-pentyloxy, i-pentyloxy, neopentyloxy,2,2-dimethylpropoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy,1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxy,1,2,2-trimethyl-n-propoxy and 3,3-dimethyl-n-butoxy, etc.

Preferably, there may be mentioned methoxy, ethoxy, n-propoxy andi-propoxy.

As C₁₋₆ alkylcarbonyloxy groups, there may be mentionedmethylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy,i-propylcarbonyloxy, n-butylcarbonyloxy, i-butylcarbonyloxy,s-butylcarbonyloxy, t-butylcarbonyloxy, 1-pentylcarbonyloxy,2-pentylcarbonyloxy, 3-pentylcarbonyloxy, i-pentylcarbonyloxy,neopentylcarbonyloxy, t-pentylcarbonyloxy, 1-hexylcarbonyloxy,2-hexylcarbonyloxy, 3-hexylcarbonyloxy, 1-methyl-n-pentylcarbonyloxy,1,1,2-trimethyl-n-propylcarbonyloxy, 1,2,2-trimethyl-n-propylcarbonyloxyand 3,3-dimethyl-n-butylcarbonyloxy, etc.

Preferably, there may be mentioned methylcarbonyloxy, ethylcarbonyloxy,n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy andt-butylcarbonyloxy.

As C₃₋₆ cycloalkyl groups, there may be mentioned cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, etc.

Preferably, there may be mentioned cyclopropyl, cyclobutyl andcyclohexyl.

As C₁₋₆ alkylcarbonyl groups, there may be mentioned methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, i-propyl-carbonyl, n-butylcarbonyl,i-butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, 1-pentylcarbonyl,2-pentylcarbonyl, 3-pentyl-carbonyl, i-pentylcarbonyl,neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyland 3-hexylcarbonyl.

Preferably, there may be mentioned methylcarbonyl, ethylcarbonyl,n-propylcarbonyl, i-propylcarbonyl and n-butylcarbonyl.

As C₁₋₆ alkylaminocarbonyl groups, there may be mentionedmethylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,i-propylaminocarbonyl, n-butylaminocarbonyl, i-butylamino-carbonyl,s-butylaminocarbonyl, t-butylaminocarbonyl, 1-pentylaminocarbonyl,2-pentylaminocarbonyl, 3-pentylaminocarbonyl, i-pentylaminocarbonyl,neopentylaminocarbonyl, t-pentylaminocarbonyl, 1-hexylaminocarbonyl,2-hexylaminocarbonyl and 3-hexylaminocarbonyl, etc.

Preferably, there may be mentioned methyaminocarbonyl,ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl andn-butylaminocarbonyl.

As di-C₁₋₆ alkylaminocarbonyl groups, there may be mentioneddimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl,di-i-propylaminocarbonyl, di-c-propylaminocarbonyl,di-n-butylaminocarbonyl, di-i-butylaminocarbonyl,di-s-butylaminocarbonyl, di-t-butylaminocarbonyl,di-2-pentylaminocarbonyl, di-3-pentylaminocarbonyl,di-i-pentylaminocarbonyl, di-neopentylaminocarbonyl,di-t-pentylaminocarbonyl, di-c-pentylaminocarbonyl,di-1-hexylaminocarbonyl, di-2-hexylaminocarbonyl anddi-3-hexylaminocarbonyl, etc.

Preferably, there may be mentioned dimethylaminocarbonyl,diethylaminocarbonyl, di-n-propylaminocarbonyl,di-i-propylaminocarbonyl, di-c-propylaminocarbonyl anddi-n-butylaminocarbonyl.

As C₁₋₆ alkoxycarbonyl groups, there may be mentioned methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl,i-butoxycarbonyl, s-butoxy carbonyl, t-butoxycarbonyl,1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl,i-pentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl,1-hexyloxycarbonyl, 2-hexyloxycarbonyl and 3-hexyloxycarbonyl, etc.

Preferably, there may be mentioned methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl,i-butoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl.

As aryl groups, there may be mentioned phenyl, biphenyl, naphthyl,anthryl and phenanthryl etc.

Preferably, there may be mentioned phenyl, biphenyl and naphthyl.

As heteroaryl groups, there may be mentioned 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-benzofuranyl,3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl,7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl,2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl,6-benzothienyl, 7-benzothienyl, 1-isobenzothienyl, 4-isobenzothienyl,5-isobenzothienyl, 2-chromenyl, 3-chromenyl, 4-chromenyl, 5-chromenyl,6-chromenyl, 7-chromenyl, 8-chromenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1-indolizinyl,2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl,7-indolizinyl, 8-indolizinyl, 1-isoindolyl, 4-isoindolyl, 5-isoindolyl,1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl,7-indolyl, 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl,5-indazolyl, 6-indazolyl, 7-indazolyl, 1-purinyl, 2-purinyl, 3-purinyl,6-purinyl, 7-purinyl, 8-purinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl,7-isoquinolyl, 8-isoquinolyl, 1-phthalazinyl, 5-phthalazinyl,6-phthalazinyl, 2-naphthyridinyl, 3-naphthyridinyl, 4-naphthyridinyl,2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 2-quinazolinyl,4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl,8-quinazolinyl, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl,7-cinnolinyl, 8-cinnolinyl, 2-pterdinyl, 4-pteridinyl, 6-pteridinyl,7-pteridinyl and 3-furazanyl, etc.

Preferably, there may be mentioned 2-pyridyl, 3-pyridyl and 4-pyridyl,etc.

As C₁₋₆ alkylamino groups, there may be mentioned methylamino,ethylamino, n-propylamino, i-propylamino, c-propylamino, n-butylamino,i-butylamino, s-butylamino, t-butylamino, c-butylamino, 1-penylamino,2-pentylamino, 3-pentylamino, i-pentylamino, neopentylamino,t-pentylamino, c-pentylamino, 1-hexylamino, 2-hexylamino, 3-hexylamino,c-hexylamino, 1-methyl-n-pentylamino, 1,1,2-trimethyl-n-propylamino,1,2,2-trimethyl-n-propylamino and 3,3-dimethyl-n-butylamino, etc.

Preferably, there may be mentioned methylamino, ethylamino,n-propylamino, i-propylamino and n-butylamino.

As di-C₁₋₆ alkylamino groups, there may be mentioned dimethylamino,diethylamino, di-n-propylamino, di-i-propylamino, di-c-propylamino,di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino,di-c-butylamino, di-1-pentylamino, di-2-pentylamino, di-3-pentylamino,di-i-pentylamino, di-neopentylamino, di-t-pentylamino, di-c-pentylamino,di-1-hexylamino, di-2-hexylamino, di-3-hexylamino, di-c-hexylamino,di-(1-methyl-n-pentyl)amino, di-(1,1,2-trimethyl-n-propyl)amino,di-(1,2,2-trimethyl-n-propyl)amino, di-(3,3-dimethyl-n-butyl)amino,methyl(ethyl)amino, methyl(n-propyl)amino, methyl(i-propyl)amino, methyl(c-propyl)amino, methyl(n-butyl)amino, methyl(i-butyl)amino,methyl(s-butyl)amino, methyl(t-butyl)amino, methyl(c-butyl)amino,ethyl(n-propyl)amino, ethyl(i-propyl)amino, ethyl(c-propyl)amino,ethyl(n-butyl)amino, ethyl(i-butyl)amino, ethyl(s-butyl)amino,ethyl(t-butyl)amino, ethyl(c-butyl amino, n-propyl(i-propyl)amino,n-propyl(c-propyl)amino, n-propyl(n-butyl)amino, n-propyl(i-butyl)amino,n-propyl(s-butyl)amino, n-propyl(t-butyl)amino, n-propyl(c-butyl)amino,i-propyl(c-propyl)amino, i-propyl(n-butyl)amino, i-propyl(i-butyl)amino,i-propyl(s-butyl)amino, i-propyl(t-butyl)amino, i-propyl(c-butyl)amino,c-propyl(n-butyl)amino, c-propyl(i-butyl)amino, c-propyl(s-butyl)amino,c-propyl(t-butyl)amino, c-propyl(c-butyl)amino, n-butyl(i-butyl)amino,n-butyl(s-butyl)amino, n-butyl(t-butyl)amino, n-butyl(c-butyl)amino,i-butyl(s-butyl)amino, i-butyl(t-butyl)amino, i-butyl(c-butyl)amino,s-butyl(t-butyl)amino, s-butyl(c-butyl)amino and t-butyl(c-butyl)amino,etc.

Preferably, there may be mentioned dimethylamino, diethylamino,di-n-propylamino, di-i-propylamino and di-n-butylamino.

As C₁₋₆ alkylcarbonylamino groups, there may be mentionedmethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino,i-propylcarbonylamino, n-butylcarbonylamino, i-butylcarbonylamino,s-butylcarbonylamino, t-butylcarbonylamino, 1-pentyl-carbonylamino,2-pentylcarbonylamino, 3-pentylcarbonylamino, i-pentylcarbonylamino,neopentylcarbonylamino, t-pentyl-carbonylamino, 1-hexylcarbonylamino,2-hexylcarbonylamino and 3-hexylcarbonylamino, etc.

Preferably, there may be mentioned methylcarbonylamino,ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino andn-butylcarbonylamino.

As C₁₋₆ alkylsulfonylamino groups, there may be mentionedmethylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,i-propylsulfonylamino, n-butylsulfonylamino, i-butylsolfonylamino,s-butylsulfonylamino, t-butylsulfonylamino, 1-pentylsulfonylamino,2-pentylsulfonylamino, 3-pentylsulfonylamino, i-pentylsulfonylamino,neopentylsulfonylamino, t-pentyl sulfonylamino, 1-hexylsulfonylamino,2-hexylsulfonylamino and 3-hexylsulfonylamino, etc.

Preferably, there may be mentioned methylsulfonylamino,ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino andn-butylsulfonylamino.

As C₁₋₆ alkylsulfonyl groups, there may be mentioned methanesulfonyl andethanesulfonyl.

As arylcarbonyl groups, there may be mentioned benzoyl, p-methylbenzoyl,p-t-butylbenzoyl, p-methoxybenzoyl, p-chlorobenzoyl, p-nitrobenzoyl andp-cyanobenzoyl.

Preferably, there may be mentioned benzoyl, p-nitrobenzoyl andp-cyanobenzoyl.

As preferable compounds used in the present invention, the followingcompounds may be mentioned.

(1) A 4-oxybenzopyran derivative of the formula (I) or pharmaceuticallyacceptable salt thereof, wherein R¹ and R² represent both methyl groupsand R³ represents a hydroxyl group.

(2) A 4-oxybenzopyran derivative or pharmaceutically acceptable saltaccording to the aforementioned (1), wherein R⁶ represents a hydrogenatom or a nitro group.

(3) A 4-oxybenzopyran derivative or pharmaceutically acceptable saltthereof according to the aforementioned (2), wherein X represents—C(═O)NH—, —C(═O)NMe—, —S(O)₂NH— or —NHC(═O)NH—.

(4) A 4-oxybenzopyran derivative or pharmaceutically acceptable saltthereof according to the aforementioned (3), wherein X represents—C(═O)NH— and R⁵ represents

(5) A 4-oxybenzopyran derivative or pharmaceutically acceptable saltthereof according to the aforementioned (4), wherein R⁴ represents aC₁₋₆ alkyl group.

Specific examples of the compounds that can be used in the presentinvention are shown as follows, but the present invention is not limitedthereto. Herein, “Me” means a methyl group, “Et” means an ethyl group,“Pr” means a propyl group, “Bu” means a butyl group, “Pen” means apentyl group, “Hex” means a hexyl group, “Ph” means a phenyl group, “Ac”means an acetyl group (COCH₃), and “−” means a bond, respectively.

TABLE 1

R¹ R² R³ R⁴ R⁶ n Me Me OH H H 1 H H OH c-Pr H 1 Me Me OH c-Hex H 2 Me MeOH Me H 1 Me Me OH Et H 1 Me Me OH n-Pr H 1 Me Me OH i-Pr H 1 Me Me OHn-Bu H 2 Me Me OH n-Pen H 3 Me Me OH n-Hex H 4 Me Me OH COMe H 2 Me MeOH CONHMe H 2 Me Me OH CONMe₂ H 2 Me Me OCOMe CF₃ H 2 Me Me OCOEt CH₂PhNO₂ 2 Me Me OH CH₂CH₂Ph NO₂ 1 Me Me OH CH₂CH₂Ph NO₂ 2 Me Me OH CH₂CH₂PhNO₂ 3 Me Me OH CH₂CH₂Ph NO₂ 4 Et Et OH CH₂CH₂Ph NO₂ 2 n-Pr n-Pr OHCH₂CH₂Ph NO₂ 2 i-Pr i-Pr OH CH₂CH₂Ph NO₂ 2 n-Bu n-Bu OH CH₂CH₂Ph NO₂ 2i-Bu i-Bu OH CH₂CH₂Ph NO₂ 2 t-Bu t-Bu OH CH₂CH₂Ph NO₂ 3 n-Pen n-Pen OHCH₂CH₂Ph NO₂ 3 n-Hex n-Hex OH CH₂CH₂Ph NO₂ 3 CF₃ CF₃ OH CH₂CH₂Ph NO₂ 3CH₂OCH₃ CH₂OCH₃ OH CH₂CH₂Ph NO₂ 3

TABLE 2

R¹ R² R³ R⁴ R⁶ n H H OH H H 0 Me Me OH c-Pr H 1 Me Me OH c-Hex H 2 Me MeOH Me Cl 3 Me Me OH Et Br 4 Me Me OH n-Pr H 0 Me Me OH i-Pr H 1 Me Me OHn-Bu H 2 Me Me OH n-Pen H 3 Me Me OH n-Hex F 4 Me Me OH COMe NO₂ 2 Me MeOH CONHMe NO₂ 2 Me Me OH CONMe₂ NO₂ 2 Me Me OCOMe CF₃ H 2 Me Me OCOEtCH₂Ph CN 2 Me Me OH CH₂CH₂Ph CN 1 Me Me OH CH₂CH₂Ph CN 2 Me Me OHCH₂CH₂Ph CN 3 Me Me OH CH₂CH₂Ph CN 4 Et Et OH CH₂CH₂Ph CN 2 n-Pr n-Pr OHCH₂CH₂Ph CN 2 i-Pr i-Pr OH CH₂CH₂Ph CN 2 n-Bu n-Bu OH Ph CN 2 i-Bu i-BuCH Ph F 2 t-Bu t-Bu OH Ph F 3 n-Pen n-Pen OH Ph Cl 3 n-Hex n-Hex OH PhCl 3 CF₃ CF₃ OH Ph Br 3 CH₂OCH₃ CH₂OCH₃ OH Ph Br 3

TABLE 3

R¹ R² R³ R⁴ R⁶ n H H OH H H 0 Me Me OH c-Pr H 1 Me Me OH c-Hex H 2 Me MeOH Me H 3 Me Me OH Et H 4 Me Me OH n-Pr H 0 Me Me OH i-Pr H 1 Me Me OHn-Bu H 2 Me Me OH n-Pen H 3 Me Me OH n-Hex H 4 Me Me OH COMe H 2 Me MeOH CONHMe H 2 Me Me OH CONMe₂ H 2 Me Me OCOMe CF₃ H 2 Me Me OCOEt CH₂PhNO₂ 2 Me Me OH CH₂CH₂Ph NO₂ 1 Me Me OH CH₂CH₂Ph NO₂ 2 Me Me OH CH₂CH₂PhNO₂ 3 Me Me OH CH₂CH₂Ph NO₂ 4 Et Et OH CH₂CH₂Ph NO₂ 2 n-Pr n-Pr OHCH₂CH₂Ph NO₂ 2 i-Pr i-Pr OH CH₂CH₂Ph NO₂ 2 n-Bu n-Bu OH CH₂CH₂Ph NO₂ 2i-Bu i-Bu OH CH₂CH₂Ph NO₂ 2 t-Bu t-Bu OH CH₂CH₂Ph NO₂ 3 n-Pen n-Pen OHCH₂CH₂Ph NO₂ 3 n-Hex n-Hex OH CH₂CH₂Ph NO₂ 3 CF₃ CF₃ OH CH₂CH₂Ph NO₂ 3CH₂OCH₃ CH₂OCH₃ OH CH₂CH₂Ph NO₂ 3

TABLE 4

R¹ R² R³ R⁴ R⁶ n H H OH H H 0 Me Me OH c-Pr H 1 Me Me OH c-Hex H 2 Me MeOH Me H 3 Me Me OH Et H 4 Me Me OH n-Pr H 0 Me Me OH i-Pr H 1 Me Me OHn-Bu H 2 Me Me OH n-Pen H 3 Me Me OH n-Hex H 4 Me Me OH COMe H 2 Me MeOH CONHMe H 2 Me Me OH CONMe₂ H 2 Me Me OCOMe CF₃ H 2 Me Me OCOEt CH₂PhNO₂ 2 Me Me OH CH₂CH₂Ph NO₂ 1 Me Me OH CH₂CH₂Ph NO₂ 2 Me Me OH CH₂CH₂PhNO₂ 3 Me Me OH CH₂CH₂Ph NO₂ 4 Et Et OH CH₂CH₂Ph NO₂ 2 n-Pr n-Pr OHCH₂CH₂Ph NO₂ 2 i-Pr i-Pr OH CH₂CH₂Ph NO₂ 2 n-Bu n-Bu OH CH₂CH₂Ph NO₂ 2i-Bu i-Bu OH CH₂CH₂Ph NO₂ 2 t-Bu t-Bu OH CH₂CH₂Ph NO₂ 3 n-Pen n-Pen OHCH₂CH₂Ph NO₂ 3 n-Hex n-Hex OH CH₂CH₂Ph NO₂ 3 CF₃ CF₃ OH CH₂CH₂Ph NO₂ 3CH₂OCH₃ CH₂OCH₃ OH CH₂CH₂Ph NO₂ 3

TABLE 5

R⁴ R⁶ R¹² n H H p-MeO 0 c-Pr H p-MeO 1 c-Hex H p-MeO 1 Me Cl p-MeO 1 EtBr p-MeO 1 n-Pr H m-MeO 1 i-Pr H o-MeO 1 n-Bu H p-Me 1 n-Pen H p-Et 1n-Hex F m-Et 1 COMe NO₂ o-Et 1 CONHMe NO₂ p-Cl 2 CONMe₂ NO₂ p-F 2 CF₃ Hp-Ph 3 CH₂Ph CN p-OH 3 CH₂CH₂Ph CN p-NO₂ 4 CH₂CH₂Ph CN p-CN 1 CH₂CH₂PhCN p-NMe₂ 1 CH₂CH₂Ph CN p-NHMe 1 CH₂CH₂Ph CN p-CO₂H 1 CH₂CH₂Ph CNm-CO₂Et 1 CH₂CH₂Ph CN m-OMe 1 CH₂CH₂Ph CN p-NO₂ 1 CH₂CH₂Ph F p-NMe₂ 1CH₂CH₂Ph F p-NHMe 1 CH₂CH₂Ph Cl p-NH₂ 2 CH₂CH₂Ph Cl p-Et 2 CH₂CH₂Ph Brp-Pr 2 CH₂CH₂Ph Br p-CH₂OMe 2

TABLE 6

R⁴ R⁶ R¹² n H H p-MeO 0 c-Pr H p-MeO 1 c-Hex H p-MeO 1 Me Cl p-MeO 1 EtBr p-MeO 1 n-Pr H m-MeO 1 i-Pr H o-MeO 1 n-Bu H p-Me 1 n-Pen H p-Et 1n-Hex F m-Et 1 COMe NO₂ o-Et 1 CONHMe NO₂ p-Cl 2 CONMe₂ NO₂ p-F 2 CF₃ Hp-Ph 3 CH₂Ph CN p-OH 3 CH₂CH₂Ph CN p-NO₂ 4 CH₂CH₂Ph CN p-CN 1 CH₂CH₂PhCN p-NMe₂ 1 CH₂CH₂Ph CN p-NHMe 1 CH₂CH₂Ph CN p-CO₂H 1 CH₂CH₂Ph CNm-CO₂Et 1 CH₂CH₂Ph CN m-OMe 1 CH₂CH₂Ph CN p-NO₂ 1 CH₂CH₂Ph F p-NMe₂ 1CH₂CH₂Ph F p-NHMe 1 CH₂CH₂Ph Cl p-NH₂ 2 CH₂CH₂Ph Cl p-Et 2 CH₂CH₂Ph Brp-Pr 2 CH₂CH₂Ph Br p-CH₂OMe 2

TABLE 7

R⁴ R⁶ R¹² n H H p-MeO 0 c-Pr H p-MeO 1 c-Hex H p-MeO 1 Me Cl p-MeO 1 EtBr p-MeO 1 n-Pr H m-MeO 1 i-Pr H o-MeO 1 n-Bu H p-Me 1 n-Pen H p-Et 1n-Hex F m-Et 1 COMe NO₂ o-Et 1 CONHMe NO₂ p-Cl 2 CONMe₂ NO₂ p-F 2 CF₃ Hp-Ph 3 CH₂Ph CN p-OH 3 CH₂CH₂Ph CN p-NO₂ 4 CH₂CH₂Ph CN p-CN 1 CH₂CH₂PhCN p-NMe₂ 1 CH₂CH₂Ph CN p-NHMe 1 CH₂CH₂Ph CN p-CO₂H 1 CH₂CH₂Ph CNm-CO₂Et 1 CH₂CH₂Ph CN m-OMe 1 CH₂CH₂Ph CN p-NO₂ 1 CH₂CH₂Ph F p-NMe₂ 1CH₂CH₂Ph F p-NHMe 1 CH₂CH₂Ph Cl p-NH₂ 2 CH₂CH₂Ph Cl p-Et 2 CH₂CH₂Ph Brp-Pr 2 CH₂CH₂Ph Br p-CH₂OMe 2

TABLE 8

R¹ R² R⁴ R⁶ n H H H H 0 Me Me c-Pr H 1 Me Me c-Hex H 1 Me Me Me Cl 1 MeMe Et Br 1 Me Me n-Pr H 1 Me Me i-Pr H 1 Me Me n-Bu H 1 Me Me n-Pen H 1Me Me n-Hex F 1 Me Me COMe NO₂ 1 Me Me CONHMe NO₂ 2 Me Me CONMe₂ NO₂ 2Me Me CF₃ H 3 Me Me CH₂Ph CN 3 Me Me CH₂CH₂Ph CN 4 Me Me CH₂CH₂Ph NO₂ 1Me Me CH₂CH₂Ph NO₂ 2 Me Me CH₂CH₂Ph NO₂ 3 Et Et CH₂CH₂Ph CN 1 n-Pr n-PrCH₂CH₂Ph CN 1 i-Pr i-Pr CH₂CH₂Ph CN 1 n-Bu n-Bu CH₂CH₂Ph CN 1 i-Bu i-BuCH₂CH₂Ph F 1 t-Bu t-Bu CH₂CH₂Ph F 1 n-Pen n-Pen CH₂CH₂Ph Cl 2 n-Hexn-Hex CH₂CH₂Ph Cl 2 CF₃ CF₃ CH₂CH₂Ph Br 2 CH₂OCH₃ CH₂OCH₃ CH₂CH₂Ph Br 2

TABLE 9

R¹ R² R⁴ R⁶ n H H H H 0 Me Me c-Pr H 1 Me Me c-Hex H 1 Me Me Me Cl 1 MeMe Et Br 1 Me Me n-Pr H 1 Me Me i-Pr H 1 Me Me n-Bu H 1 Me Me n-Pen H 1Me Me n-Hex F 1 Me Me COMe NO₂ 1 Me Me CONHMe NO₂ 2 Me Me CONMe₂ NO₂ 2Me Me CF₃ H 3 Me Me CH₂Ph CN 3 Me Me CH₂CH₂Ph CN 4 Me Me CH₂CH₂Ph NO₂ 1Me Me CH₂CH₂Ph NO₂ 2 Me Me CH₂CH₂Ph NO₂ 3 Et Et CH₂CH₂Ph CN 1 n-Pr n-PrCH₂CH₂Ph CN 1 i-Pr i-Pr CH₂CH₂Ph CN 1 n-Bu n-Bu CH₂CH₂Ph CN 1 i-Bu i-BuCH₂CH₂Ph F 1 t-Bu t-Bu CH₂CH₂Ph F 1 n-Pen n-Pen CH₂CH₂Ph Cl 2 n-Hexn-Hex CH₂CH₂Ph Cl 2 CF₃ CF₃ CH₂CH₂Ph Br 2 CH₂OCH₃ CH₂OCH₃ CH₂CH₂Ph Br 2

TABLE 10

R⁴ R⁶ R¹² R^(12′) n H H Br Br 0 c-Pr H Br Br 1 c-Hex H Br Br 1 Me Cl BrMeO 1 Et Br Br Br 1 n-Pr H Br Br 1 i-Pr H Br MeO 1 n-Bu H Br MeO 1 n-PenH Br MeO 1 n-Hex F Br MeO 1 COMe NO₂ Br MeO 1 CONHMe NO₂ Br MeO 2 CONMe₂NO₂ Br Br 2 CF₃ H Br Br 3 CH₂Ph CN Br Br 3 CH₂CH₂Ph CN Br Br 4 CH₂CH₂PhNO₂ Br Br 1 CH₂CH₂Ph CN Br MeO 1 CH₂CH₂Ph NO₂ Br MeO 1 CH₂CH₂Ph CN Cl Cl1 CH₂CH₂Ph NO₂ Cl Cl 1 CH₂CH₂Ph NO₂ Cl Cl 2 CH₂CH₂Ph CN Cl MeO 1CH₂CH₂Ph F Cl McO 1 CH₂CH₂Ph F Cl MeO 2 CH₂CH₂Ph Cl Cl MeO 1 CH₂CH₂Ph ClCl MeO 2 CH₂CH₂Ph Br Cl MeO 1 CH₂CH₂Ph Br Cl MeO 2

TABLE 11

R¹ R² R⁹ R⁶ n H H p-MeO H 0 Me Me p-MeO H 1 Me Me p-MeO H 2 Me Me p-MeOH 3 Me Me H H 1 Me Me m-MeO H 0 Me Me o-MeO H 1 Me Me p-Me H 2 Me Mep-Et H 3 Me Me m-Et H 4 Me Me o-Et H 2 Me Me p-Cl H 2 Me Me p-F H 2 MeMe p-Ph H 2 Me Me p-OH NO₂ 2 Me Me p-NO₂ NO₂ 1 Me Me p-CN NO₂ 2 Me Mep-NMe₂ NO₂ 3 Me Me p-NHMe NO₂ 4 Et Et p-CO₂H NO₂ 2 n-Pr n-Pr m-CO₂Et NO₂2 i-Pr i-Pr m-OMe NO₂ 2 n-Bu n-Bu p-NO₂ NO₂ 2 i-Bu i-Bu p-NMe₂ NO₂ 2t-Bu t-Bu p-NHMe NO₂ 3 n-Pen n-Pen p-NH₂ NO₂ 3 n-Hex n-Hex p-Et NO₂ 3CF₃ CF₃ p-Pr NO₂ 3 CH₂OCH₃ CH₂OCH₃ p-CH₂OMe NO₂ 3

TABLE 12

R⁴ R⁶ R¹² n H H p-MeO 1 Me H p-MeO 1 Et NO₂ p-MeO 1 n-Pr NO₂ p-MeO 1 EtH p-MeO 4 i-Pr H m-MeO 0 i-Pr H o-MeO 1 CH₂CH₂Ph H p-MeO 1 n-Pen H p-Et3 n-Hex H m-Et 4 COMe H o-Et 2 CONHMe H p-Cl 2 CONMe₂ H p-F 2 CF₃ H p-Ph2 CH₂Ph NO₂ p-OH 2 CH₂CH₂Ph NO₂ p-MeO 1 Ph NO₂ p-MeO 1 CH₂Ph NO₂ p-MeO 1H NO₂ p-MeO 1 Me NO₂ p-MeO 1 CH₂CH₂Ph NO₂ m-CO₂Et 1 CH₂CH₂Ph NO₂ m-OMe 1CH₂CH₂Ph NO₂ p-NO₂ 1 CH₂CH₂Ph NO₂ p-NMe₂ 1 CH₂CH₂Ph NO₂ p-NHMe 1CH₂CH₂Ph NO₂ p-NH₂ 1 CH₂CH₂Ph NO₂ p-Et 1 CH₂CH₂Ph NO₂ p-Pr 1 CH₂CH₂PhNO₂ p-CH₂OMe 1

The compound according to the present invention has asymmetric carbonatoms at 3-position and 4-positon, thus optical isomers thereof based onthe asymmetric carbon atoms are present, which can be used in theapplication of the present invention similar to racemate thereof.Further, a cis or trans isomer based on configuration at 3-position and4-position may be included, but the trans isomer is preferable.

Further, when the compounds can form their salts, the pharmaceuticallyacceptable salts can be also used as active ingredients.

As pharmaceutically acceptable salts, there may be mentionedhydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates,benzoates, tartrates, phosphates, lactates, maleates, fumarates,malates, gluconates and salicylates, etc.

Preferably, there may be mentioned hydrochlorides and methanesulfonates.

Then, the preparation method of the compound according to the presentinvention is illustrated.

Of the compounds of the general formula (I), those wherein R³ representsa hydroxyl group, which are the compounds of formula (I-a), can beobtained by reacting a compound of the general formula (2) with acompound (3) in an inert solvent, as shown in the following reactionscheme.

The compound of the general formula (2) can be synthesized according toknown methods (methods described in J. M. Evans et al., J. Med. Chem.1984, 27, 1127, J. Med. Chem. 1986, 29, 2194, J. T. North et al., J.Org. Chem. 1995, 60, 3397, as well as Japanese Patent ApplicationLaid-Open No. Sho 56-57785, Japanese Patent Application Laid-Open No.Sho 56-57786, Japanese Patent Application Laid-Open No. Sho 58-188880,Japanese Patent Application Laid-Open No. Hei 2-141, Japanese PatentApplication Laid-Open No. Hei 10-87650 and Japanese Patent ApplicationLaid-Open No. Hei 11-209366, etc.).

In this scheme, R¹ ,R² ,R⁴ ,R⁵ ,R⁶ ,x and n are as defined above.

As the solvents used in the reaction of the compound of the generalformula (2) with the compound (3), the following may be mentioned.

There may be mentioned sulfoxide type solvents exemplified bydimethylsulfoxide; amide type solvents exemplified by dimethylformamideor dimethylacetamide; either type solvents exemplified by ethyl ether,dimethoxyethane or tetrahydrofuran; halogen type solvents exemplified bydichloromethane, chloroform and dichloroethane; nitrile type solventsexemplified by acetonitrile and propionitrile; aromatic hydrocarbon typesolvents exemplified by benzene and toluene; hydrocarbon type solventsexemplified by hexane and heptane; and ester type solvents exemplifiedby ethyl acetate. Further, the reaction can be carried out in theabsence of a solvent. Preferably, ether type solvents and nitrile typesolvents may be mentioned.

The reaction temperature is generally from −80° C. to the refluxtemperature of the reaction solvent, preferably from −10° C. to 100° C.

The molar ratio of the reaction materials is within the range of0.5-20.0, preferably 1.0-10.0, for the compound (3)/the compound (2).

An acid catalyst may be used in the reaction.

As the acid catalysts used, there may be mentioned inorganic acidsexemplified by hydrochloric acid and sulfuric acid, as well as Lewisacids exemplified by aluminum chloride, titanium tetrachloride, borontrifluoride diethyl ether complex, perchloric acid, lithium perchlorateand ytterbium trifluoromethanesulfonate, etc.

Preferably, there may be mentioned sulfuric acid and perchloric acid.

Of the compounds of the general formula (I), those other than thecompounds of formula (I-a) described above (those of the formula (I)wherein R³ represents a C₁₋₆ alkylcarbonyloxy group) can be prepared bythe preparation methods similar to those described in Japanese PatentApplication Laid-Open No. Sho 52-91866 and Japanese Patent ApplicationLaid-Open No. Hei 10-87650, etc.

Syntheses of optically active compounds included in the compounds of thegeneral formula (I) can be attained by utilizing optical resolutionmethods (Japanese Patent Application Laid-Open No. Hei 3-141286, U.S.Pat. No. 5,097,037 and European Patent No. 409165). Further, synthesesof optically active compounds of the general formula (2) can be attainedby utilizing asymmetrical synthetic methods (Japanese NationalPublication No. Hei 5-507645, Japanese Patent Application Laid-Open No.Hei 5-301878, Japanese Patent Application Laid-Open No. Hei 7-285983,European Patent Application Laid-open No. 535377, and U.S. Pat. No.5,420,314).

As described above, we, inventors, found that the compound of thegeneral formula (I) has the strong prolongation effect on the functionalrefractory period. The prolongation effect on the functional refractoryperiod is one of the functions of antiarrhythmic action and an importantindicator that can be extrapolated to efficiency for clinicalarrhythmia. Conventional antiarrhythmic agents having the prolongationeffect on the functional refractory period as the main function (such asd-sotalol belonging to Class III of the antiarrhythmic agentclassification according to Vaughan Williams) have quite dangerousarrhythmic inducing actions that can result in sudden death such astorsades de pointes based on extension of ventricular muscle actionpotential relating to the prolongation effect on the functionalrefractory period, which become the therapeutic problems for arrhythmiabased on atrium (such as supraventricular tachycardia, atrial flutterand atrial fibrillation). In order to solve the problems, we, inventors,carried out searching and studying of compounds having the prolongationeffect on the functional refractory period more selective for atriummuscle than for ventricular muscle, and found that the compound of thegeneral formula (I) has the prolongation effect on the functionalrefractory period selective for atrium muscle without any influence onthe functional refractory period of ventricular muscle and actionpotential parameters. The difference between the present invention bythe inventors and the known techniques is to provide the prolongationeffect on the functional refractory period selective for atrium muscleby the compound, which is shown by the following facts; without anyinfluence on the action potential sustaining period of removedventricular muscle and without any influence on the electrocardiogram QTof anesthetized animal. From the above, the compounds of the presentinvention have no arrhythmic inducing action in ventricular muscle, thusthey can provide possibilities of more safe uses for arrhythmia based onatrium muscle than known techniques. The technique according to thepresent invention is useful for therapeutic or preventive uses asanti-atrial fibrillation agents, anti-atrial flutter agents andanti-atrial tachycardia agents relating to paroxysmal, chronic,preoperative, intraoperative of postoperative atrial arrhythmia,prevention of proceeding to embolus based on atrial arrhythmia,prevention of proceeding to ventricular arrhythmia or tachycardiaoriginated from atrial arrhythmia or tachycardia, and prevention of thelife prognosis worsening based on the preventive action for atrialarrhythmia or tachycardia which can be proceeded to ventriculararrhythmia or tachycardia.

The present invention provides a pharmaceutical composition orveterinary pharmaceutical composition containing the compound of thegenerally formula (I) in an effective amount for these treatments.

As administering forms of the compound according to the presentinvention, there may be mentioned parenteral administrations by means ofinjections (subcutaneous, intravenous, intramuscular and intraperitonealinjections), ointments, suppositories and aerosol, or oraladministration by means of tablets, capsules, granules, pills, syrups,solutions, emulsions and suspensions, etc.

The above-mentioned pharmaceutical or veterinary pharmaceuticalcomposition contains the compound according to the present invention inan amount of about 0.01-99.5%, preferably about 0.1-30%, of the totalcomposition weight.

In addition to the compound according to the present invention or thecomposition containing the compound, other pharmaceutically orveterinary pharmaceutically active compounds may be contained.

Further, these compositions may contain the plurality of compoundsaccording to the present invention.

A clinical administration amount varies depending on age, weight andsensitivity of the patient, extent of condition of the patient, etc. andan effective administration amount is generally about 0.003-1.5 g,preferably 0.01-0.6 g, per day for adult. If necessary, however, theamount outside of the above-mentioned range may be used.

The compound according to the present invention is formulated foradministration by conventional pharmaceutical means.

That is, tablets, capsules, granules and pills for oral administrationare prepared by using excipients such as sucrose, lactose, glucose,starch and mannitol; binders such as hydrozypropyl cellulose, syrup, gumarabic, gelatin, sorbitol, tragacanth, methyl cellulose and polyvinylpyrrolidone; disintegrators such as starch, carboxymethyl cellulose orits calcium salt, crystal cellulose powder and polyethylene glycol;lubricants such as talc, magnesium or calcium stearate, and silica;lubricaing agents such as sodium laurate and glycerol, etc.

Injections, solution, emulsions, suspension, syrups and aerosols areprepared by using solvent for the active ingerdients such as water,ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycoland polyethylene glycol; surfactants such as sorbitan fatty acid ester,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acidester, polyoxyethylene ether of hydrogenated castor oil and lecithin;suspending agents such as carboxymethyl sodium salt, cellulosederivatives such as methyl cellulose, tragacanth, and natural rubberssuch as gum arabic; and preserves such as p-hydroxybenzoic acid esters,benzalkonium chloride and sorbic acid salts, etc.

For ointments that are transdermally adsorptive pharmaceutics, whitevaseline, liquid paraffin, higher alcohols, Macrogol ointments,hydrophilic ointments and aqueous gel-type bases are, for example, used.

Suppositories are prepared by using, for example, cocoa fats,polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil andPolysorbate etc.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in detail by the Examples asfollows, but the present invention is not limited to these Examples.

Synthesis Examples Synthesis example 1

(3R*,4S*)-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-7-nitro-2H-1-benzopyran-3,4-diol

To a mixed solution of (3R*, 4R*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-7-nitro-2H-1-benzopyran(the synthetic method of which is described in Japanese Patent Laid-OpenPublication No. Hei 10-87650) 300 mg, 0.78 mmol, 99% ee, [α]_(D) ²⁵+6l2(C 0.70, CHCl₃)) in acetonitrile (2mL) and a 70% aqueous perchloricacid solution (1 mL), water (1mL) was added at the room temperature andstirred at the room temperature for 2 hours. After adding a 10% aqueoussodium carbonate solution to the solution, an aqueous saturated sodiumchloride solution was added. Then the resulting solution was extractedwith ethyl acetate, and dried over anhydrous sodium sulfate. After thesolvent was distilled off, the residue was recrystallized (frommethanol-water), to obtain the intended substance (yield: 81%).

¹H-NMR (CDCl₃) δ: 1.27 (s, 3H), 1.46 (s, 3H), 3.60-3.65 (m, 1H), 3.37(s, 2H), 3.79 (s, 3H), 3.90-3.94 (m, 2H), 4.60-4.62 (m, 1H), 6.95 (d,J=8.6 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.57 (s, 1H), 8.79 (s, 1H), 9.93(s, 1H).

MS (EI) m/z; 402[M]⁺, 356, 254, 182, 148, 122 (bp).

The following compounds were obtained in the similar manner.

Synthesis example 2

(3R*,4S*)-3,4-dihydro-2,2-dimethyl-4-methoxy-6-(4-methoxyphenylacetylamino)-7-nitro-2H-1-benzopyran-3-ol

Yield:39%

¹H-NMR (CDCl₃) δ: 1.27 (s, 3H), 1.46 (s, 3H), 2.34 (m, 1H), 3.64 (s,3H), 3.73 (s, 2H), 3.83 (s, 3H), 3.80-3.85 (m, 1H), 4.31-4.34 (m, 1H),6.95 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.58 (s, 1H), 8.75 (s,1H), 9.9 (s, 1H).

MS (EI) m/z; 416[M]⁺, 268, 148, 121 (bp). ; mp. 104° C.

Synthesis example 3

(3R*,4S*)-4-ethoxy-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-7-nitro-2H-1-benzopyran-3-ol

Yield:53%

Orange amorphous substance

¹H-NMR (CDCL₃) δ: 1.27 (s, 3H), 1.35 (t, J=7.0 Hz, 3H), 1.46 (s, 3H),2.33 (m, 1H), 3.73 (s, 2H), 3.83 (s, 3H), 3.76-4.0 (m, 3H), 4.36 (d,J=7.9 Hz, 1H), 6.96 (d, J=8.6 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.57 (s,1H), 8.78 (s, 1H), 9.93 (s, 1H).

MS (EI) m/z; 430[M]⁺, 282, 148, 121 (bp).

Synthesis Example 4

(3R*,4S*)-3,4-dihydro-2,2-dimethyl-4-propoxy-6-(4-methoxyphenylacetylamino)-7-nitro-2H-1-benzopyran-3-ol

Yield:40%

mp. 115-116° C.

¹H-NMR (CDCl₃) δ: 1.01 (t, J=7.4 Hz, 3H), 1.27 (s, 3H), 1.45 (s, 3H),1.73 (q, J=6.6 Hz, 2H), 2.35 (m, 1H), 3.73 (s, 2H), 3.68-3.85 (m, 4H),3.83 (s, 3H), 6.95 (d, J=8.6 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.57 (s,1H), 8.78 (s, 1H), 9.92 (s, 1H).

MS (EI) m/z; 444[M]⁺, 296, 148, 121 (bp).

Synthesis Example 5

Trans-3,4-dihydro2,2-dimethyl-6-(4-methoxyphenylacetylamino)-4-(2-phenylethoxy)-2H-1-benzopyran-3-ol

To a solution of3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-2H-1-benzopyran(200 mg, 0.68 mmol) and phenethyl alcohol (0.32 mL, 2.72 mmol) inacetonitrile (1.0 mL), sulfuric acid (0.01 mL) was added and stirred atthe room temperature for 2 hours. Thereto, ice-cooled ethyl acetate wasadded and the formed crystals were filtered, to obtain the intendedsubstance as white solid (yield:77%).

m.p.:161.0-162.0° C.

¹H-NMR (CDCl₃) δ: 1.17 (s, 3H), 1.35 (s, 3H), 2.93 (t, 2H, J=6.4 Hz),3.64 (d,1H, J=7.6 Hz), 3.66 (s,2H), 3.83 (s, 3H), 3.84-3.90 (m, 1H),3.94-3.99 (m, 1H), 4.29 (d, 1H, J=7.6 Hz), 6.68 (d, 2H, J=8.8 Hz), 6.84(s, 1H), 6.94 (d, 2H, J=8.8 Hz), 7.11 (d, 1H, J=2.4 Hz), 7.19-7.32 (m,6H).

MS (EI) m/z; 461[M]⁺, 389, 340, 192 (bp).

The following compounds were obtained in the similar manner.

Synthesis Example 6

Trans-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenyl)acetylamino-7-nitro-4-(2-phenylethoxy)-2H-1-benzoypyran-3-ol

mp.:125.2-125.5° C.

¹H-NMR (CDCl₃) δ: 1.17 (s, 3H), 1.36 (s, 3H), 1.84 (d, J=4.0 Hz, 1H),2.98-3.01 (m, 2H), 3.60 (dd, J=4.0, 8.2 Hz, 1H), 3.74 (s, 2H), 3.83 (s,3H), 3.90-3.96 (m, 1H), 4.15-4.21 (m, 1H) 4.32 (dd, J=0.9, 8.2 Hz, 1H),6.94-7.55 (m, 10H), 8.76 (d, J=0.9 Hz, 1H), 9.89 (bs, 1H)

MS (EI) m/z; 507 [m]⁺, (bp), 358.

Synthesis Example 7

Trans-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenyl)acetylamino-7-nitro-4-phenyloxy-2H-1-benzopyran-3-ol

mp.:178.0-178.6° C.

¹H-NMR (DMSO-d₆)δ: 1.31 (s, 3H), 1.37 (s, 3H), 3.52 (s, 2H), 3.72 (s,3H), 3.77 (dd, J=5.7, 6.0 Hz, 1H), 5.31 (d, J=6.0 Hz, 1H), 5.92 (d,J=5.7 Hz, 1H), 6.86-7.48 (m, 11H), 10.126 (bs, 1H)

MS (EI) m/z; 478 [M]⁺, 237 (bp).

Synthesis Example 8

Trans-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenyl)acetylamino-4-nitro-4-benzyloxy-2H-1-benzopyran-3-ol

mp.:117.8-119.1° C.

¹H-NMR (DMSO-d₆) δ: 1.24 (s, 3H), 1.38 (s, 3H), 3.56 (s, 2H), 3.74 (s,3H), 3.77-3.80 (m, 1H), 4.48 (d, J=7.0 Hz, 1H), 4.80 (d, J=11.4 Hz, 1H),5.78 (d, J=5.7 Hz, 1H), 6.88-7.58 (m, 11H), 10.15 (bs, 1H) MS (EI) m/z;492[M]⁺, 123 (bp).

Synthesis Example 9

Trans-3,4-dihydro-2,2-dimethyl-7-nitro-4-(2-phenylethoxy-6-(4-methoxyurea)-2H-1-benzopyran-3-ol

¹H-NMR (CDCl₃) δ: 1.18 (s, 3H), 1.36 (s, 3H), 2.95-2.98 (m, 2H),3.59-3.60 (m, 1H), 3.89-3.95 (m, 1H), 4.13 (d, J=8.4 Hz, 1H) 4.29 (d,J=8.4 Hz, 1H), 7.13-7.54 (m, 12H), 8.53 (s, 1H), 9.50 (s, 1H)

MS (EI) m/z; 477 [M]⁺, (bp), 120.

Preparation Examples Preparation Example 1

Tablet: a compound according to the invention 10 g lactose 260 g crystalcellulose powder 600 g corn starch 350 g hydroxypropyl cellulose 100 gCMC—Ca 150 g magnesium stearate 30 g total 1,500 g

The above-mentioned compounds were mixed by a usual method andthereafter 10,000 sugar-coated tablets each containing 1 mg of theactive ingredient per a tablet were prepared.

Preparation Example 2

Capsule: a compound according to the invention 10 g lactose 440 gcrystal cellulose powder 1,000 g magnesium stearate 50 g total 1,500 g

The above-mentioned compounds were mixed by a usual method andthereafter filled in gelatin capsules, to prepare 10,000 capsules eachcontaining 1 mg of the active ingredient per a capsule.

Preparation Example 3

Soft capsule: a compound according to the invention 10 g PEG 400 479 gsaturated fatty acid triglyceride 1,500 g peppermint oil 1 g Polysorbate80 10 g Total 2,000 g

The above-mentioned compounds were mixed by a usual method andthereafter filled in No. 3 soft gelatin capsules, to prepare 10,000 softcapsules each containing 1 mg of the active ingredient per a capsule.

Preparation Example 4

Ointment: a compound according to the invention 1.0 g liquid paraffin10.0 g cetanol 20.0 g white vaseline 68.4 g ethylparaben 0.1 g 1-menthol0.5 g total 100.0 g

The above-mentioned compounds were mixed by a usual method to obtain 1%ointment.

Preparation Example 5

Suppository: a compound according to the invention 1 g Witepsol H15* 478g Witepsol W35* 520 g Polysorbate 80 1 g Total 1,000 g (*trade nameWitepsol for triglyceride type compounds)

The above-mentioned compounds were melt-mixed by a usual method, pouredinto suppository containers and cooled to solidify, thereby 1,000suppositories (1 g) each containing 1 mg of the active ingredient per asuppository were prepared.

Preparation Example 6

Injection: a compound according to the invention 1 mg distilled waterfor injection 5 mL

It is used by dissolving when applied.

Pharmacological Test Example Effects of Compound on the FunctionalRefractory Period in Guinea-pig Left Atrium Muscle and Right VentricularPapillary Muscle

Test method

Hearts were removed from guinea-pigs, and left atrium muscle or rightventricular papillary muscle were isolated therefrom in aKrebs-Henseleit solution aerated with 95% O₂+5% CO₂. The samples werestimulated electrically at a rate of 1 Hz and a voltage of 1.5 times ofthe threshold value reacted to stimulation (basic stimulation; S1) byusing an electric stimulating apparatus. The contraction occurred atthat time was recorded by a thermal stylus recorder via a FD pickup anda strain pressure amplifier. The functional refractory period is definedas the shortest time interval between S1 resulting from determinablecontraction and an extra stimulation (S2). The time interval between S1and S2 in the left atrium muscle sample was started from 150 msec,decreased in 10 msec steps until 100 msec, and thereafter 5 msec stepsto the functional refractory period. For the right ventricular papillarymuscle sample, it was started from 300 msec and decreased in 10 msecsteps until the functional refractory period. Herein, S2 was set attwice of the threshold value which reacted to stimulation. Theexperimental temperature was 36±1° C. Herein, the solvent did notinfluence of any of the functional refractory periods for left atriummuscle and right ventricular papillary muscle. After determining thebasic value before addition of the compound, the compound was addedcumulatively, incubated for 15 minutes for respective concentration, andthereafter the functional refractory period was determined.

Results

Compounds according to the present invention exhibited strongprolongation effect on the functional refractory period(FRP) on atriummuscle.

TABLE 13 Synthesis Prolongation example effect on FRP No. EC₂₀ (μM) 62.4 9 21.9

Compounds according to the present invention exhibit strong prolongationeffect on the functional refractory period, thus they are useful forimprovement of arrhythmia. Therefore, the present invention can provideuseful antiarrhythmic agents.

What is claimed is:
 1. A 4-oxybenzopyran derivative of the formula (I)

wherein, R¹ and R² represent each independently a hydrogen atom; a C₁₋₆alkyl group in which said alkyl group may be optionally substituted witha halogen atom, a C₁₋₆ alkoxy group or a hydroxyl group; of a phenylgroup in which said phenyl group may be optionally substituted with ahalogen atom, a hydroxyl group, a nitro group, a cyano group, a C₁₋₆alkyl group or a C₁₋₆ alkoxy group; R³ represents a hydroxyl group or aC₁₋₆ alkylcarbonyloxy group; R⁴ represents a hydrogen atom, a C₃₋₆cycloalkyl group, a C₁₋₆ alkyl group, a C₁₋₆ akylcarbonyl group, a C₁₋₆alkylaminocarbonyl group or a di-C₁₋₆ alkylaminocarbonyl group in whichsaid C₁₋₆ alkyl group, said C₁₋₆ alkylcarbonyl group, said C₁₋₆alkylaminocarbonyl group and said di-C₁₋₆ alkylaminocarbonyl group maybe each optionally substituted with a halogen atom, a C₁₋₆ alkoxy group,a C₁₋₆ alkoxy group substituted by a halogen atom; a carboxyl group, aC₁₋₆ alkoxycarbonyl group, a hydroxyl group, or an aryl group or aheteroaryl group, in which said aryl group and said heteroaryl group maybe optionally substituted with (R⁹)_(r), in which R⁹ represents ahalogen atom, a hydroxyl group, a C₁₋₆ alkyl group, a C₁₋₆ alkyl groupsubstituted by a halogen atom or a C₁₋₆ alkoxy group; a C₁₋₆ alkoxygroup, a C₁₋₆ alkoxy group substituted by a halogen atom; or R⁹represents a nitro group, a cyano group, a formyl group, a formamidegroup, an amino group, a C₁₋₆ alkylamino group, a di-C₁₋₆ alkylaminogroup, a C₁₋₆ alkylcarbonylamino group, A C₁₋₆ alkylsulfonylamino group,an aminocarbonyl group, a C₁₋₆ alkylaminocarbonyl group, a di-C₁₋₆alkylaminocarbonyl group, a C_(1≢)alkylcarbonyl group, a C₁₋₆alkoxycarbonyl group, an aminosulfonyl group, a C₁₋₆ alkylsulfonylgroup, a carboxyl group or an arylcarbonyl group, r represents aninteger of 1-3 and each R⁹ may same or different if r represents 2 or 3;or R⁴ represents an aryl group or a heteroaryl group in which said arylgroup and said heteroaryl group may be optionally substituted with(R¹⁰)_(q) in which R¹⁰ has the same meaning as R⁹, q represents aninteger of 1-3, and each R¹⁰ may be same or different if q represents 2or 3; n represents an integer of 0-4; X represents —C(═O)NR⁷—, —NR⁸—,—NHC(═O)NH— or —S(O)₂NH— (in which R⁷ and R⁸ represent eachindependently a hydrogen atom or a C₁₋₆ alkyl group); R⁵ represents ahydrogen atom; or a group of the formula:

in which R¹² represents a hydrogen atom; a halogen atom; a C₁₋₆ alkylgroup in which the alkyl group may be optionally substituted with ahalogen atom or a C₁₋₆ alkoxy group; a C₁₋₆ alkoxy group in which saidalkoxy group may be optionally substituted with a halogen atom; a phenylgroup in which said phenyl group may be optionally substituted with ahalogen atom, a hydroxyl group, a C₁₋₆ alkyl group or a C₁₋₆ alkoxygroup or R¹² represents a hydroxyl group, a nitro group, a cyano group,a formyl group, a formamide group, an amino group, a C₁₋₆ alkylaminogroup, a di-C₁₋₆ alkylamino group, a C₁₋₆ alkylcarbonylamino group, aC₁₋₆ alkylsulfonylamino group, an aminocarbonyl group, a C₁₋₆alkylaminocarbonyl group, a di-C₁₋₆ alkylaminocarbonyl group, a C₁₋₆alkylcarbonyl group, a C₁₋₆ alkoxycarbonyl group, an aminosulfonylgroup, a C₁₋₆ alkylsulfonyl group, a carboxyl group or an arylcarbonylgroup, m represents an integer of 1-3, and each R¹² may be same ordifferent if m represents 2 or 3, and R¹³ represents a hydrogen atom ora C₁₋₆ alkyl group; and R⁶ represents a hydrogen atom, a halogen atom, anitro group or a cyano group; or a pharmaceutically acceptable saltthereof.
 2. A 4-oxybenzopyran derivative or pharmaceutically acceptablesalt thereof according to claim 1, wherein R¹ and R² represent bothmethyl groups and R³ represents a hydroxyl group.
 3. A 4-oxybenzopyranderivative or pharmaceutically acceptable salt according to claim 2,wherein R⁶ represents a hydrogen atom or a nitro group.
 4. A4-oxybenzopyran derivative or pharmaceutically acceptable salt thereofaccording to claim 3, wherein X represents —C(═O)NH—, —C(═O)NMe—,—S(O)₂NH— or —NHC(═O)NH—.
 5. A 4-oxybenzopyran derivative orpharmaceutically acceptable salt thereof according to claim 4, wherein Xrepresents —C(═O)NH— and R⁵ represents


6. A 4-oxybenzopyran derivative or pharmaceutically acceptable saltthereof according to claim 5, wherein R⁴ represents a C₁₋₆ alkyl group.7. A drug characterized by comprising a 4-oxybenzopyran derivative orpharmaceutically acceptable salt thereof according to claim 1 as anactive ingredient.
 8. A drug for treating arrhythmia characterized bycomprising a 4-oxybenzopyran derivative or pharmaceutically acceptablesalt thereof according to claim 1 as an active ingredient.